Central nervous system (CNS) trauma, caused by injuries such as spinal and head injuries, are becoming more prevalent. Many of these injuries are caused by common events such as automobile accidents, serious falls, diving accidents, crushing industrial injuries and gunshot or stab wounds.
Traumatic brain or spinal cord injuries cause tissue damage through both direct and indirect, or secondary, means. Direct tissue damage is typically caused by direct mechanical injury to the tissue. Secondary tissue damage is believed to be caused by the activation of endogenous, autodestructive, neurochemical substances. Other types of acute CNS injuries, such as stroke or hypoxia, also exhibit secondary tissue damage that shares many of the secondary injury factors associated with neurotrauma.
Thyrotropin-releasing hormone (TRH), which has been identified as L-pyroglutamyl-L-histidyl-L-prolinamide, is a small peptide that has been found in various cells of the body, mainly in the neural cells of the CNS. The structure of TRH is shown below:

The right portion of the molecule is known to those of skill in the art as the “prolinamide” portion; the center portion of the molecule is known as the “histidyl” or “imidazole ring” portion; and the left portion of the molecule is known as the “pyroglutamyl” portion.
Endogenous TRH can act as a neurotransmitter, a neuromodulator or both. A major percentage of TRH is released from the hypothalamic nerve terminals in the median eminence to stimulate the secretion of thyroid stimulating hormone, the function for which TRH is named. TRH is also found in other areas of the CNS, and in tissues of the body such as the alimentary tract, pancreas, placenta and retina.
The function of TRH in these various areas of the body is largely unknown. However, numerous physiological actions in addition to the hypophysiotrophic function for which TRH is named have been observed. For example, TRH has autonomic and analeptic effects (Yarborouh et al., 1979, Prog. Neurobiol. 12:291–312), as well as the ability to reverse or attenuate certain physiological effects of opioids (Holaday et al., 1978, Life Sci. 22:1537–1543), neurotensin (Prange et al., 1979, In: Central Nervous System Effects of Hypothalamic Hormones and Other Peptides, pp. 75–96, Raven, N.Y.), leukotrienes (Lux et al., 1983, Nature 302:822–824) and platelet-activating factor (Lux et al., 1983, Circ. Shock 10:262). TRH administration reduces neurological deficits after traumatic spinal cord injury in cats (Faden et al., 1981, N. Engl. J. Med. 305:1063–1067). Additionally, treatment with TRH has also been found to improve electrical activity and neurological recovery in cats subjected to brainstem compression (Fukuda et al., 1979, Folia Pharmacol. Jpn. 75:321–331), and to shorten postconcussional behavioral suppression following head impact trauma in mice (Manaka and Sano, 1978, Neurosci. Lett. 8:255–258). One of the advantages of TRH is that it acts as a physiological opiate antagonist without affecting nociception.
However, as a drug to treat CNS trauma, TRH has several drawbacks. The major disadvantage is that TRH is very rapidly metabolized. As a consequence, high doses and/or continuous infusions are necessary for effective treatment. The short plasma half-life (4–5 min.) is most likely due to rapid in vivo degradation or metabolism of the peptide at both the prolineamide and pyroglutamyl portions of the molecule. Cleavage of the pyroglutamyl moiety of TRH by peptidases causes the formation of the metabolite cyclo-histidyl-proline-diketopiperazine. Deamidation of TRH results in the formation of the free acid TRH-OH.
Because of the drawbacks of TRH, two classes of compounds have been studied: cyclic dipeptides and azetidinones. The cyclicdipeptides [also known as bicyclic 2,5-dioxopiperazines; bicyclic 2,5-diketopiperazines; cyclo(dipeptides); or dipeptide anhydrides] are generally based upon observed metabolite products of TRH. The azetidones are based upon TRH in which the pyroglutamyl portion has been replaced with 2-azetidinone.
Cleavage of the amino-terminal pyroglutamic acid from TRH by pyroglutamyl aminopeptidase followed by cyclization of His-Pro-NH2 yields the metabolite cyclo(His-Pro) (Prasad & Peterkofsky, 1976, J. Biol. Chem. 251:3229–3234; Prasad et al., 1977, Nature 268:142–144). Cyclo(His-Pro), as well as certain other cyclic dipeptides have been tested for biological activity. However, of those tested, only four—cyclo(His-Pro), cyclo(Leu-Gly), cyclo(Tyr-Arg) and cyclo(Asp-Pro)—exhibit any biological activity in mammals (for a review of the activities of various cyclic dipeptides see Prasad et al., 1995, Peptides 16(1):151–164, and the references cited therein). Of these, none has been identified as being useful as a neuroprotective agent or to treat neurological disorders such as Alzheimer's disease.
GB 2 127 807 discloses certain 2-5-diketo-piperazines useful for inhibiting the development of tolerance to the cataleptic effect after repeated administration of neuroleptics, and for the treatment of memory disturbance, tardive dyskenesias and Parkinson's disease. DD 153208 discloses certain 2,5-diketopiperazines that are potentially useful as synthetic ergot alkaloids. DD 246767 discloses the cyclic dipeptide cyclo(Lys-Pro), and pharmaceutical compositions thereof, that are useful as stimulants of nerve fiber growth and nerve cell differentiation and maintenance. JP 63135386 describes certain hydroxyproline cyclic dipeptides useful as plant growth accelerators. However, none of these compounds has been identified as being useful as a neuroprotectant or to treat neurological disorders such as Alzheimer's disease.
Modification of one or more of the constituent amino acids of TRH has led to the development of various TRH analogues, some of which are highly resistant to enzymatic degradation and are far more potent than TRH with respect to CNS activity (Metcalf, 1982, Brain Research 486:389–408). The advantage of such compounds in CNS injury is that they may permit utilization of lower drug concentrations and single parenteral dosing (Faden, “Role of TRH and Opiate Receptor Antagonists in Limiting Central Nervous System Injury,” In: Physiological Basis for Functional Recovery in Neurological Disease, S. Waxman, Ed., Vol. 47, Raven, N.Y., 1987, pp. 531–546).
However, only certain classes of these compounds are effective in protecting against tissue damage. For example, compounds CG3509 (Faden and Jacobs, 1985, Neurology 35:1331–1334) and CG3703 (Faden et al., 1988, Brain Research 448:287–293), which have substitutions for the pyroglutamyl moiety improve outcome following traumatic spinal cord injury (McIntosh et al., 1988, Am. J. Physiol. 254:R785–R792). In contrast, compound MK-771 (Faden and Jacobs, 1985 supra), which has modifications at both ends of the tripeptide, and compound RX-77368 (Faden et al., 1988, supra) which has a modification only at the prolineamide moiety, proved ineffective even at very high doses. Moreover, many of these analogues have been found to have centrally active effects such as endocrine, analeptic and autonomic effects (Faden, 1989, Brain Res. 486:228–235; Faden et al., 1993, J. Neurotrauma 10(2):101–108).
Faden, 1989, Brain Research 486:228–235 describes a peptidase-resistant TRH analogue called YM-14673, in which the pyroglutamyl portion of TRH is replaced with a 2-azetidinone moiety. The structure of YM-14673 is shown below:
Analogue YM-14673 is longer acting (8–36 times) and has substantially greater potency (10–100 times) with regard to central facilitating activity than TRH (Faden et al., 1989, supra). Treatment with YM-14673 also improved chronic neurological recovery in rats following trauma (Faden, 1989, supra).
U.S. Pat. No. 5,686,420 to Faden describes peptidase-resistant TRH analogues in which the imidazole ring of the histidyl moiety has been replaced with an imidazole substituted with one or more trifluoromethyl, nitro or halogen groups and/or in which the pyroglutamyl moiety has been replaced with a different ring structure, such as a 2-azetidinone moiety. An exemplary compound is an analogue of YM-14673 in which the imidazole ring is di-substituted at the 2 and 4 carbons with iodo groups. The structure of this diiodo analogue of YM-14673 is shown below:
Additional TRH analogues in which the pyroglutamyl moiety has been replaced with a 2-azetidinone moiety are described in European Patent EP 0 123 444. However, while effective, these 2-azetidinone TRH analogues exhibit undesirable autonomic and endocrine side-effects.
Thus, there remains a need in the art for compounds that are effective in treating neurological disorders, especially TRH analogues that are effective in reducing secondary brain and spinal cord injury in patients suffering from CNS injuries, that do not affect nociception, that are not rapidly metabolized by protases in vivo, and that have less endocrine and/or autonomic effects than TRH. There is also a need for compounds that improve cognitive function, especially following acute or chronic brain injuries. Accordingly, these are objects of the present invention.